The technique of precipitation by compressed antisolvents (PCA) has been used to manufacture linear-homopolymer microparticles to encapsulate a variety of materials for the controlled release of the encapsulated materials. Encapsulation of materials, particularly pharmaceutical drugs, into biodegradable polymers using PCA is attractive because of high encapsulation efficiency (Falk et al, J. Controlled Release, 44:77-85 (1997)), low residual solvent levels, low processing temperatures (Falk & Randolph, Pharmaceutical Research, 15(8):1233-1237 (1998)), and the production of micron sized particles (Randolph et al, Biotech. Progress, 9:429-435 (1993); Dixon et al., AIChE J., 39(1):127-139 (1993)).
However, the use of PCA at times produces certain undesirable results. For example, linear-homopolymers, such as poly(lactide), encapsulated microparticles release the encapsulated materials over several months, which is a relatively long period of time. Such long release times are particularly undesirable for many pharmaceutical delivery applications, because of potential adverse patient reactions. In addition, the high solubility of supercritical carbon dioxide (CO.sub.2), which enables the rapid extraction of solvent from the polymer during PCA, also causes large quantities of CO.sub.2 to diffuse into the polymer. Acting as a diluent, CO.sub.2 lowers the glass transition temperature (T.sub.g) of the polymer. Polymers susceptible to a suppression of T.sub.g below the operating temperature of the PCA system may form agglomerated particles or thin films during precipitation.
The study of CO.sub.2 effects on polymers is not new. T.sub.g suppression was originally observed in the creep rates recorded for poly(carbonate) pipes pressurized with CO.sub.2 (Hojo & Findley, Polymer Engr. Science, 13:255-265 (1973)). Eventually this behavior led to new production methods for polymer foams, the extraction of low molecular weight compounds from polymers, and the impregnation of polymers with chemical additives (Wissinger & Paulaitis, Industrial & Engr. Chem. Res., 30:842-851 (1991)). Experimental measurements of T.sub.g suppression by CO.sub.2 include observing the relaxation of mechanical properties (Wang et al., J. Polymer Sci. Part B: Polymer Physics, 20(6):1371-84 (1982)), differential scanning calorimetry (Chiou et al., J. Applied Polymer Sci., 30:2633-2642 (1985)), and creep compliance (Condo & Johnston, J. Polymer Sci: Part B: Polymer Physics, 32:523-533 (1994)). Thermodynamic models using lattice fluid theory and the Gibbs-Di Marzio criterion predict glass transition temperatures as a function of pressure remarkably well (Condo et al., Macromolecules, 25(23)6119-6127 (1992); Kalosiros & Paulaitis, Chem. Engr. Sci., 49(5):659-668 (1994)). Together, models and experiments led to the classification of four fundamental polymer behaviors, and the understanding that the T.sub.g of a polymer or copolymer at a particular pressure depends on the pure polymer T.sub.g and the solubility of CO.sub.2 within the polymer. Thus research to date on viable polymers for PCA has been limited to measuring or predicting a polymer's glass transition temperature after interaction with compressed carbon dioxide. As a result, previous theory deemed all polymers with glass transition temperatures below the operating conditions of the PCA system as unusable.
Bodmeier et al., Pharmaceutical Research, 12(8):1211-1217 (1995) reported some interesting observations while determining suitable polymers for PCA. Bodmeier et al. based the compatibility of a polymer on the degree of swelling observed in compressed CO.sub.2. From the six polymers investigated, they reported the highly crystalline and the semi-crystalline polymers were generally unaffected by high pressure CO.sub.2 exposure, while all the amorphous polymers agglomerated under similar conditions.
Poly(lactide-co-glycolide) is a common biodegradable pharmaceutical polymer. The copolymer has been extensively used for suture material and, in the last decade, has been explored as a potential drug release medium. However, the PCA technique was believed to be unsuitable for the copolymer because compressed carbon dixoide severely affects the mechanical properties of the copolymer and prevents formation of microparticles.
Accordingly, a need exists for methods of using lactide-co-glycolide copolymers in PCA to form microparticles. The present invention satisfies this need and provides related advantages.